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The functional study of different mutations on  vitamin D receptor (VDR)  gene causing hereditary vitamin D-resistant rickets (HVDRR) remains limited. This study was to determine the  VDR  mutation and the mechanisms of this mutation-causing phenotype in a family with HVDRR and alopecia. Phenotype was analyzed, and  in vitro  functional studies were performed. The proband and his affected sister exhibited typical HVDRR with alopecia, and their biochemical and radiographic abnormalities but not alopecia responded to supraphysiological doses of active vitamin D 3 . A novel homozygous missense R343H mutation in the exon 9 of  VDR  residing in the retinoid X receptor (RXR)-binding domain was identified. The expression level and C-terminal conformation of R343H mutant are not different from the wild-type VDR. This mutant had no effect on the nuclear localization of VDR, VDR-RXR heterodimerization, but it impaired  CYP24A1  promoter activity in the presence of 1,25 (OH) 2  vitamin D 3 , at least in part, mediated through specific nuclear receptor coactivator. Simulation models revealed the vanished interaction between guanidinium group of R343 and carboxyl group of E269. Without affecting the expression, conformation, nuclear location of VDR or heteridimerization with RXR, VDR-R343H impairs the transactivation activity of VDR on downstream transcription, accounting for HVDRR features with alopecia.

Functional Analysis of VDR Gene Mutation R343H in A Child with Vitamin D-Resistant Rickets with Alopecia